Marked disparity of microRNA modulation by cGMP-selective PDE5 versus PDE9 inhibitors in heart disease

Kristen M. Kokkonen-Simon, Amir Saberi, Taishi Nakamura, Mark Ranek, Guangshuo Zhu, Djahida Bedja, Michaela Kuhn, Marc K Halushka, Dong Lee, David A Kass

Research output: Contribution to journalArticle

Abstract

MicroRNAs (miRs) posttranscriptionally regulate mRNA and its translation into protein, and are considered master controllers of genes modulating normal physiology and disease. There is growing interest in how miRs change with drug treatment, and leveraging this for precision guided therapy. Here we contrast 2 closely related therapies, inhibitors of phosphodiesterase type 5 or type 9 (PDE5-I, PDE9-I), given to mice subjected to sustained cardiac pressure overload (PO). Both inhibitors augment cyclic guanosine monophosphate (cGMP) to activate protein kinase G, with PDE5-I regulating nitric oxide (NO) and PDE9-I natriuretic peptide-dependent signaling. While both produced strong phenotypic improvement of PO pathobiology, they surprisingly showed binary differences in miR profiles; PDE5-I broadly reduces more than 120 miRs, including nearly half those increased by PO, whereas PDE9-I has minimal impact on any miR (P < 0.0001). The disparity evolves after pre-miR processing and is organ specific. Lastly, even enhancing NO-coupled cGMP by different methods leads to altered miR regulation. Thus, seemingly similar therapeutic interventions can be barcoded by profound differences in miR signatures, and reversing disease-associated miR changes is not required for therapy success.

Original languageEnglish (US)
JournalJCI insight
Volume3
Issue number15
DOIs
StatePublished - Aug 9 2018

Fingerprint

Cyclic GMP
MicroRNAs
Heart Diseases
Pressure
Nitric Oxide
Phosphodiesterase 5 Inhibitors
Cyclic GMP-Dependent Protein Kinases
Natriuretic Peptides
Protein Biosynthesis
Therapeutics
Pharmaceutical Preparations
Genes
Proteins

Keywords

  • Cardiology
  • Cell Biology
  • Heart failure
  • Noncoding RNAs
  • Phosphodiesterases

Cite this

Marked disparity of microRNA modulation by cGMP-selective PDE5 versus PDE9 inhibitors in heart disease. / Kokkonen-Simon, Kristen M.; Saberi, Amir; Nakamura, Taishi; Ranek, Mark; Zhu, Guangshuo; Bedja, Djahida; Kuhn, Michaela; Halushka, Marc K; Lee, Dong; Kass, David A.

In: JCI insight, Vol. 3, No. 15, 09.08.2018.

Research output: Contribution to journalArticle

Kokkonen-Simon, Kristen M. ; Saberi, Amir ; Nakamura, Taishi ; Ranek, Mark ; Zhu, Guangshuo ; Bedja, Djahida ; Kuhn, Michaela ; Halushka, Marc K ; Lee, Dong ; Kass, David A. / Marked disparity of microRNA modulation by cGMP-selective PDE5 versus PDE9 inhibitors in heart disease. In: JCI insight. 2018 ; Vol. 3, No. 15.
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